Cytokinetics Releases Phase 1 Study Data on CK-4021586

Cytokinetics, Incorporated, a biopharmaceutical company based in South San Francisco, announced the results of their Phase 1 study of CK-4021586 (CK-586) at the American College of Clinical Pharmacology Annual Meeting. The primary and secondary objectives of the study, which included assessing the safety, tolerability, and pharmacokinetics of CK-586, were successfully met. The results pave the way for a Phase 2 clinical trial aimed at treating patients with heart failure with preserved ejection fraction (HFpEF), anticipated to commence in Q4 2024.

CK-586 is an investigational cardiac myosin inhibitor being developed to potentially address a subgroup of HFpEF patients exhibiting hypercontractility and ventricular hypertrophy. The Phase 1 study's findings are consistent with preclinical data, showing that CK-586 effectively reduces cardiac contractility by acting at the sarcomere level. Stuart Kupfer, M.D., the Chief Medical Officer, highlighted the predictable pharmacokinetic (PK) and pharmacodynamic (PD) profile of CK-586, which supports a once-daily dosing regimen for patients.

The Phase 1 study was a double-blind, randomized, placebo-controlled clinical trial involving healthy participants. It included seven single-dose cohorts (ranging from 10 mg to 600 mg) and two multiple-dose cohorts (100 mg and 200 mg daily). The trial demonstrated that CK-586 was well tolerated, with no serious adverse events reported. The half-life of CK-586 ranged between 14 to 17 hours, showing dose-linearity over a broad exposure range. Participants achieved steady-state within seven days. Key efficacy indicators, such as left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), decreased from baseline in a manner dependent on drug exposure, yet the changes were predictable and shallow. At the highest single dose of 600 mg, the reduction in LVEF was minimal, indicating promising pharmacologic properties for future fixed-dose daily administration.

CK-586 is a novel, selective small molecule that inhibits cardiac myosin ATPase activity, specifically targeting the hypercontractile state seen in HFpEF without affecting calcium transients. Preclinical models showed that CK-586 reduces the number of active myosin cross-bridges during heart muscle contraction, thus decreasing overall contractile force while improving heart muscle relaxation (lusitropy). This mechanism is particularly relevant for a subset of HFpEF patients who resemble those with non-obstructive hypertrophic cardiomyopathy (HCM) due to their higher ejection fractions and thickened heart walls. Previous studies with aficamten, another myosin inhibitor from Cytokinetics, have shown beneficial outcomes in patients with HCM, including improved patient-reported outcomes and biomarker levels.

Heart failure, affecting over 64 million people globally, is a severe condition with a poor prognosis. In the U.S. alone, approximately 6.7 million individuals suffer from heart failure, a figure expected to rise to over 8.5 million by 2030. HFpEF accounts for about half of these cases, with increasing prevalence. Despite widespread use of standard treatments, 75% of HFpEF patients die within five years of initial hospitalization, and 84% are rehospitalized. Therefore, there is a significant unmet need for effective treatments targeting this subgroup of patients.

Cytokinetics continues to lead in muscle biology-related drug development, focusing on small molecule drugs that target cardiac muscle function and contractility. In addition to CK-586, the company is advancing aficamten through various Phase 3 trials for different forms of HCM and is also developing omecamtiv mecarbil, another cardiac muscle activator, for heart failure patients.